Control of Postnatal SVZ Neurogenesis via Cholinergic Circuit Activity

 描述(由申请人提供)：尽管生物医学科学最近取得了进展，但对患有神经精神疾病的患者来说，有效的治疗选择仍然有限。虽然大多数人类病例的潜在病因和病理生理学尚不清楚，但越来越清楚的是，早期神经发育缺陷可能是晚年行为后遗症的原因之一。最近，在人类神经精神障碍的小鼠模型中，神经前体细胞的增殖和分化异常被描述出来。出生后啮齿动物侧脑室周围的脑室下区(SVZ)是一个特殊的环境，容纳着作为神经干细胞(NSCs)的GFAP+星形胶质细胞，主要产生GABA能中间神经元。出生后SVZ的神经发生受NSC内在机制的调控，与细胞外/生态位驱动的信号相互作用。人们普遍认为，这些局部效应是维持神经发生的原因，尽管行为范式和疾病状态表明可能存在更高水平的调节。目前尚不清楚神经元或离散神经回路的活动状态是否可以直接控制出生后SVZ的神经发生。我们已经确定了乙酰胆碱(ACh)由神经元终末释放到SVZ的壁龛中。我们的初步结果揭示了一个以前未描述的胆碱能神经元群体，将它们的突起直接投射到SVZ神经干细胞上。光遗传刺激或抑制这些新的胆碱能神经元可导致SVZ神经干细胞中可测量到的电流感应和神经发生速率的同步变化。我们计划通过确定以下内容来进一步探讨这些观察结果：1)哪些较高水平的脑区提供兴奋性驱动以诱导SVZ中ACh的释放；2)在ACh激活下游的SVZ NSCs中需要哪些分子机制来促进神经发生；以及3)哪些SVZ利基细胞结构/组织可以将神经元的放电频率转化为NSC的增殖和增加的神经发生。我们的研究建议探索胆碱能神经元的神经元活动与出生后SVZ NSC增殖之间的直接联系。为了使这个研究问题变得容易处理，我们开发了新的小鼠试剂，以及光遗传学和实时成像平台，以直接测量神经元活动模式和SVZ神经发生之间的相互作用。我们相信，这些发现将对我们垂直推进我们对出生后SVZ神经发生的电路水平活动控制的功能理解产生积极影响，对神经精神疾病中胆碱能回路功能障碍具有潜在的重要意义。

 DESCRIPTION (provided by applicant): Despite recent advances in biomedical sciences, effective treatment options remain limited for patients suffering from neuropsychiatric diseases. While the underlying etiology and pathophysiology remain unclear for majority of the human cases, it has become increasingly clear that early neurodevelopmental defects can be a contributor to behavioral sequelae later in life. Recently, neural progenitor proliferation and differentiation abnormalities have been described in mouse models of human neuropsychiatric disorders. The postnatal rodent subventricular zone (SVZ) niche around the lateral brain ventricles is a specialized environment housing GFAP+ astrocytes functioning as neural stem cells (NSCs), producing mainly GABAergic interneurons. Postnatal SVZ neurogenesis is regulated by NSC-intrinsic mechanisms, interacting with extracellular/niche-driven cues. It is generally believed that these local effects are responsible for sustaining neurogenesis, though behavioral paradigms and disease states have pointed to possibilities for higher-level modulation. It is currently unclear if activity states from groups of neurons, or discrete neural circuits can directly control postnatal SVZ neurogenesis. We have identified acetylcholine (ACh) release by neuronal terminals into the SVZ niche. Our preliminary results have uncovered a previously undescribed population of cholinergic neurons, projecting their processes directly onto SVZ NSCs. Optogenetic stimulation or inhibition of these novel cholinergic neurons resulted in measurable electrical current induction in SVZ NSCs and concurrent changes in the rates of neurogenesis. We plan to further explore these observations by determining the following: 1) which higher-level brain regions provide excitatory drive to induce ACh release in the SVZ; 2) what are the molecular mechanisms required in SVZ NSCs downstream of ACh activation to promote neurogenesis; and 3) which are the SVZ niche cellular structures/organizations that can transform neuronal firing frequencies into NSC proliferation and increased neurogenesis. Our study proposes to explore a direct connection between neuronal activity from cholinergic neurons and postnatal SVZ NSC proliferation. To make this research question tractable, we have developed new mouse reagents, as well as optogenetic and live-imaging platforms to directly measure the interactions between neuronal activity patterns and SVZ neurogenesis. We believe these findings will have a positive impact by vertically advancing our functional understanding of postnatal SVZ neurogenesis control by circuit-level activity, with potentially important implications for cholinergic circuit dysfunctionin neuropsychiatric diseases.